Salt of phenoxypyridine derivative or crystal thereof and process for producing the same

A technology of pyridine and oxygen, which is applied in the field of salts of phenoxypyridine derivatives and their crystallization and preparation, and can solve problems such as undisclosed or implied compounds

Inactive Publication Date: 2009-06-10
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, patent document 1 has disclosed phenoxypyridine derivatives with HGFR inhibitory effect and its preparation method, but it does not disclose or suggest Compound 1 and Compound 2, and the salts or salts of Compound 1 and Compound 2 involved in the present invention. Crystals thereof and methods for their preparation

Method used

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  • Salt of phenoxypyridine derivative or crystal thereof and process for producing the same
  • Salt of phenoxypyridine derivative or crystal thereof and process for producing the same
  • Salt of phenoxypyridine derivative or crystal thereof and process for producing the same

Examples

Experimental program
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preparation example Construction

[0074] 1. The preparation method of the crystallization of the malate of compound 1

[0075] Compound 1, a solvent, and malic acid are mixed to form a solution, and crystals are precipitated to prepare crystals of a malate salt of Compound 1.

[0076] More specifically, for example, compound 1 and a solvent are mixed at room temperature, malic acid is added at room temperature or under heating to form a solution, and the solution is gradually cooled to about 4°C to room temperature to precipitate crystals, thereby being able to Crystals of the malate salt of compound 1 were prepared. In addition, it is preferable to stir a solution while gradually cooling.

[0077] As the solvent, for example, ketones such as acetone, alcohols such as ethanol, 1-propanol, and 2-propanol can be used, and ethanol is preferable.

[0078]The amount of solvent is not particularly limited, and it is preferable to use 5 to 30 times the amount of compound 1.

[0079] The amount of malic acid can b...

preparation example 1-1

[0123] (Preparation example 1-1) ethyl 4-chloropyridine-2-carboxylate

[0124] A mixture of 4-chloropyridine-2-carboxylic acid (39.4 g) and thionyl chloride (64 ml) was stirred with heating at 100° C. for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature. It was concentrated under reduced pressure and azeotroped in toluene. The residue was added a little at a time to ice-cooled and stirred ethanol. The reaction was stirred at room temperature for 25.5 hours. The reaction solution was concentrated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure to obtain the title compound (38.8 g, 83.6%) as a brown oil.

[0125] 1 H-NMR spectrum (CDCl 3 )δ (ppm): 1.46 (3H, t, J = 7.2Hz), 4.50 (2H, q, J = ...

preparation example 1-2

[0126] (Preparation example 1-2) ethyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate

[0127]3-Fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml) were added to ethyl 4-chloropyridine-2-carboxylate (19.4 g), and it was heated at 120° C. under nitrogen atmosphere Stir for 4 hours. The reaction solution was cooled to room temperature. Ethyl acetate (400 ml) and saturated aqueous sodium carbonate solution (400 ml) were added thereto, and it was stirred at room temperature for 27 hours. Stirring was stopped and the aqueous layer was separated. Further, saturated aqueous sodium carbonate solution was added to the organic layer, which was stirred at room temperature for 2 days. Stirring was stopped and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300ml). The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, which was concentrated under reduced pressure. Th...

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Abstract

The invention provides acid addition salts of the compounds represented by formula (1) or (2), or crystals thereof, and processes for preparing the same. The salts or crystals have HGFR inhibitory activity and excellent physical properties (solubility, safety, etc.) and are therefore useful as anti-tumor agents, angiogenesis inhibitors and inhibitors for metastasis for a various types of tumor.

Description

technical field [0001] The present invention relates to a salt of a phenoxypyridine derivative useful as an antitumor agent or a cancer metastasis inhibitor, or its crystal and their method of preparation. [0002] In particular, the present invention relates to N-(2-fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridine- Acid addition of 4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (formula (1) below; hereinafter referred to as "Compound 1") salt or its crystals and N-{2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy] Salts of phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (the following formula (2); hereinafter referred to as "compound 2") or crystals thereof, and methods for producing them. [0003] Background technique [0004] It has been reported that HGFR is overexpressed in various tumors such as pancreatic cancer, gastric cancer, colorectal cancer, breast cancer, prostate ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/4427A61K31/496A61P35/00A61P35/04
CPCC07D401/14C07D401/12C07D417/14C07D413/14C07D403/12C07D213/75C07D405/12C07D239/47C07D409/14A61P35/00A61P35/04A61P43/00A61K31/4427A61K31/496
Inventor 松岛知广白鸟修司高桥惠子镰田厚若杉和纪坂口贵久
Owner EISIA R&D MANAGEMENT CO LTD
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